DESCRIPTION: (Applicant's Abstract) The candidate for the K08 award, Thomas F. Newton, M.D., has training in psychiatry and seeks to obtain additional, focused training in drug abuse research. His short term career goals are to acquire additional skills which complement ongoing pharmacologic challenge studies. His longer term career goals are to develop a research program aimed at better understanding of the relationships between brain substrates for drugs of abuse, the clinical effects of abused drugs, and treatments for drug dependence. The candidate proposes a five year training program aimed at developing the skills necessary to complete a series of research projects in human stimulant abuse and dependence. The training program will emphasize the development of skills necessary to investigate: (a) neurochemistry and neurophysiology, using PET in humans, (b) pharmacology related to stimulant dependence, and c) pharmacokinetics. The research project presented in detail aims at determining (a) whether dopamine transporter (DAT) availability, assessed by WIN binding in the striatum, is reduced in methamphetamine dependent subjects compared to a normal control population; (b) to determine the temporal subjective and physiologic dose-response profile of intravenous d- methamphetamine (MeAmp), compared to intravenous saline, in MeAmp dependent subjects; and c) to determine the association between DAT availability and response to intravenous MeAmp dependent subjects, in order to better define the role of the DA transporter in stimulant dependence. A career development plan is proposed which aims to dissect out neurochemical and neurophysiological abnormalities underlying stimulant dependence by investigation of abnormalities in several neurotransmitter systems, alterations in brain metabolic activity, and impairments in neurocognitive function. The significance of specific abnormalities will be explored (where possible) by studying stimulant dependent subjects with defined abnormalities in the experimental pharmacology laboratory using challenge studies.